Diseases associated with viral infection, such as viral hepatitis, influenza infection, herpesviral infection, AIDS, and viral hemorrhagic fever, are recognized as medically and socially important problems. For the diseases associated with viral infection, preventions using vaccines and the like, and therapies using drugs, for example, are widely studied. However, it cannot be said that such vaccines and drugs produce sufficient effects, and furthermore elucidation of their action mechanisms per se may be difficult in some viruses so that development of drugs against such viruses still cannot be started. In addition, since traits of viruses are extremely diverse and transcription factors etc. involved in their life cycles are also varied, the development of drugs is currently underway for individual viruses.
Hepatitis B virus (hereinafter abbreviated as “HBV”), one of the causes of diseases associated with virus infection, is thought to affect more than 350 million people worldwide. HBV causes acute or chronic hepatitis after infection, and some of the hepatitis cases further progress to hepatic cirrhosis or hepatic cancer. Currently, interferons (IFNs) and nucleotide analogs are used in the treatment of hepatitis B caused by HBV. However, it is difficult to completely eliminate the virus even in patients receiving long-term administration of such agents, and furthermore, there are problems with the agents, such as occurrence of resistant viruses and acute exacerbations in patients receiving long-term administration, increase in severity due to re-exacerbation after completion of administration, and the like.
After HBV enters a hepatocyte, the viral genes move into the nucleus of the hepatocyte, and then converted from incompletely circular double-stranded DNA into Hepatitis B virus covalently closed circular DNA (HBV cccDNA). It is known that HBV cccDNA is bare closed circular HBV DNA that is present in the nucleus of hepatocytes and acts as a replicative intermediate during viral replication (Non-Patent Document 1). In hepatocytes, HBV cccDNA behaves in the same manner as the human genome and stays in the nucleus. It is also known that HBV cccDNA is not directly affected by an antiviral nucleotide analog and still remains in hepatocytes after nucleotide analog therapy. It is a clinical fact that HBV viral genome cannot be completely eliminated from hepatocytes with existing agents, and therefore radical cure of HBV infection is thought to be impossible (Non-Patent Document 2).
Since HBV cccDNA has the property of staying within the cell after HBV infection, it has attracted attention in recent years as a marker for prediction of long-term prognosis for antiviral drugs and degree of liver damage. However, the in vivo mechanism of retaining HBV after infection has not yet been elucidated, and also the behavior of HBV cccDNA remains unclear. As a drug focusing on HBV cccDNA, an artificial DNA nuclease targeting HBV cccDNA itself has been reported (Patent Document 1).
For complete removal of HBV from hepatocytes to prevent or treat hepatitis B, there is a great need for elucidating HBV retention mechanism including behavior of cccDNA and thereby discovering a new molecule(s) that can be a target of anti-HBV drug.